Objective: MicroRNAs (miRNAs) from mesenchymal stem cells (MSC)-derived extracellular vesicles (MSCs-EVs), including exosomes, are known to participate in different diseases. However, the function of miR-301b-3p from MSCs-EVs on the chemoresistance of gastric cancer (GC) cells remains poorly characterized. Thus, we aim to explore the role of MSCs-EVs-derived miR-301b-3p in multidrug resistance of GC cells.
Methods: Cisplatin (DDP)/vincristine (VCR)-resistant and sensitive GC clinical samples were harvested to detect expression of miR-301b-3p and thioredoxin interacting protein (TXNIP). MSCs were respectively transfected with miR-301b-3p oligonucleotides and/or TXNIP plasmids to extract the EVs, which were then co-cultured with multidrug-resistant GC cells. Then, P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), IC50, proliferation, migration, and apoptosis of resistant GC cells were determined. The tumor growth was observed in nude mice. Targeting relationship between miR-301b-3p and TXNIP was confirmed.
Results: miR-301b-3p was upregulated, and TXNIP was downregulated in DDP/VCR-resistant GC tissues and cells. MSC-EVs induced drug resistance, proliferation, and migration and inhibited apoptosis of DDP/VCR-resistant GC cells in vitro, as well as facilitated tumor growth in vivo. Inhibition of miR-301b-3p or upregulation of TXNIP reversed the promoting effect of MSC-EVs on DDP/VCR resistant GC cells to DDP/VCR resistance and malignant behaviors. The effects of MSC-EVs carrying miR-301b-3p inhibition on DDP/VCR-resistant GC cells were reversed by TXNIP downregulation. TXNIP was confirmed as a target gene of miR-301b-3p.
Conclusion: miR-301b-3p from MSCs-EVs inhibits TXNIP to promote multidrug resistance of GC cells, providing a novel insight for chemotherapy in GC.
Keywords: Gastric cancer; Mesenchymal stem cell-derived exosome; MicroRNA-301b-3p; Multidrug resistance; Thioredoxin interacting protein.
© 2022. The Author(s), under exclusive licence to Springer Nature B.V.